Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine

The aim of the present study was to evaluate the influence of glutathione (GSH), the thiomer chitosan4-thiobutylamidine (chitosan-TBA) and a combination of both compounds on P-glycoprotein (P-gp) activity. Permeation studies were performed with freshly excised guinea pig ileum mounted in Ussing chambers using the fluorescent dye rhodamine- 123 (Rho-123) as P-gp substrate. Apparent permeability coefficients (P-app) as well as efflux ratios (secretory P-app/absorptive P-app) were calculated and compared with values gained from experiments with the well-established P-gp inhibitors terfenadine and verapamil. In the presence of terfenadine, verapamil as well as GSH, the absorptive transport of Rho-123 across intestinal tissue increased, while the secretory decreased with efflux ratios around 1.0. Chitosan-TBA and especially chitosan-TBA/GSH not only enhanced absorption of Rho- 123, but also reduced the basolateral to apical secretion of Rho-123 resulting in efflux ratios of 1.1, 0.8 and 0.5. The study indicates that chitosan-TBA/ GSH is a potentially valuable tool for inhibiting the ATPase activity of P-gp in the intestine. (c) 2005 Elsevier B.V. All rights reserved.